Although salivary secretions are primarily regulated by the autonomic nervous system, there is evidence that other factors may modulate the secretory functions of salivary glands. These include the prostaglandins, which are ubiquitous, biologically active fatty acid derivatives which affect a great variety of tissues and physiological functions. The overall, long-term objective of this project is, therefore, to characterize the role that PG play as modulators of salivary gland function. To initiate our characterization of this modulation, we propose studies for this grant period designed to investigate the effects of two major prostaglandins (PGE1 and PGF2alpha) and of substances involved in their metabolism (arachidonic acid, phospholipase A2, phosphatidic acid) on several aspects of the mechanism underlying the secretion of salivary fluid and electrolytes. Using the rat submandibular gland as the model system, we propose to first characterize the effects of a wide range of doses of these substances on fluid and electrolyte secretion induced by cholinergic and adrenergic agents in isolated, perfused gland preparations. Effects on saliva volumes, rates of flow, electrolyte (Na, K, C1, Ca) composition and outputs and fractional ductal reabsorption and secretion will be investigated. Second, based on what is currently known about the ionic mechanism underlying the formation of saliva, we propose to investigate the effects of the PG and related substances on ion movements in dispersed submandibular acini isolated by enzymatic digestion of the gland. We are particularly interested in those ion movements which are part of the mechanism leading to saliva secretion. These include: a) release and uptake of K+; b) uptake and efflux of Cl; c) uptake and efflux of Ca++. Isotopic tracers of these ions will be used to study the effects of the test substances on various kinetic parameters, including the time course of the respective flux, the half time for isotope equilibration, the initial rate (i.e., rate constants) and the maximum flux (Jmax). Correlations between the findings of both types of experiment should provide more detailed information about the manner in which PG modulate a major aspect of secretory function in salivary glands, namely, the secretion of fluid and electrolytes (the aqueous fraction of saliva). This can provide clues about the role of these substances in altering salivary gland function in pathological conditions (inflammation, immune reactions) in which their tissue levels are disturbed by the disease process.